title: Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: phosphorylated signal transducer and activator of transcription 3- and phosphatidylinositol 3-kinase-mediated inhibition.
abstract: BACKGROUND
  The possibility of restoring sevoflurane postconditioning (sevo-postC) cardioprotection in diabetic animals is uncertain. We hypothesized that attenuation of myocardial injury by sevo-postC might be hindered by inhibition of signal transducer and activator of transcription (STAT) 3-regulated activity of phosphatidylinositol 3-kinase (PI3K) in diabetic animals. To determine whether postC cardioprotection can be restored by normoglycemia, we treated rats with insulin.
  
  
  METHODS
  Diabetic or nondiabetic rats were randomly subjected to 30-min ischemia/reperfusion, with ischemic postC or sevo-postC, with and without mitochondrial adenosine triphosphate-dependent potassium channel blocker 5-hydroxy decanoate sodium and PI3K antagonist wortmannin. The infarct area, phosphorylated STAT3, and apoptosis were examined. Studies were repeated after insulin treatment.
  
  
  RESULTS
  Ischemic postC and sevo-postC significantly reduced infarct size by 50% in the nondiabetic rats (P < 0.002), a phenomenon completely reversed by 5-hydroxy decanoate sodium and wortmannin. Diabetes mellitus blocked the protective effect of postC, and insulin treatment to achieve normoglycemia did not restore cardioprotection. Phosphorylated STAT3 nuclear retention was significantly increased after ischemia-reperfusion and was further enhanced in response to ischemic postC (P < 0.05) but was significantly reduced in diabetic rats (by 43%; P < 0.01).
  
  
  CONCLUSIONS
  The effective reduction in infarct size and apoptosis in the nondiabetic rat heart by postC was completely abrogated in diabetic rats. This inhibition is not relieved by insulin-induced normoglycemia. The PI3K pathway and mitochondrial adenosine triphosphate-dependent potassium channel activation are involved in the mechanism of postC. In diabetic rats, STAT3 activation was strongly reduced, as was postC cardioprotection, suggesting that the inability of insulin to restore postC may be attributed to diabetes-induced STAT3-mediated inhibition of PI3K signaling.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. drenger@cc.huji.ac.il
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drenger
authors.forename: Israel A
authors.initials: IA
authors.lastname: Ostrovsky
authors.forename: Michal
authors.initials: M
authors.lastname: Barak
authors.forename: Yael
authors.initials: Y
authors.lastname: Nechemia-Arbely
authors.forename: Ehud
authors.initials: E
authors.lastname: Ziv
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Axelrod
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D057775:Ischemic Postconditioning / Q000379:methods; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077149:Sevoflurane; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D007328:Insulin; D008738:Methyl Ethers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor; D000077149:Sevoflurane; D058539:Phosphatidylinositol 3-Kinase; D000077191:Wortmannin